.2021 May 21;372(6544):815-821.

doi: 10.1126/science.abh2644. Epub 2021 Apr 14.

Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil

Nuno R Faria^#^{1 2 3 4}, Thomas A Mellan^#^{5 2}, Charles Whittaker^#^{5 2}, Ingra M Claro^#^{3 6}, Darlan da S Candido^#^{3 4}, Swapnil Mishra^#^{5 2}, Myuki A E Crispim^{7 8}, Flavia C S Sales^{3 6}, Iwona Hawryluk^{5 2}, John T McCrone⁹, Ruben J G Hulswit¹⁰, Lucas A M Franco^{3 6}, Mariana S Ramundo^{3 6}, Jaqueline G de Jesus^{3 6}, Pamela S Andrade¹¹, Thais M Coletti^{3 6}, Giulia M Ferreira¹², Camila A M Silva^{3 6}, Erika R Manuli^{3 6}, Rafael H M Pereira¹³, Pedro S Peixoto¹⁴, Moritz U G Kraemer⁴, Nelson Gaburo Jr¹⁵, Cecilia da C Camilo¹⁵, Henrique Hoeltgebaum¹⁶, William M Souza¹⁷, Esmenia C Rocha^{3 6}, Leandro M de Souza^{3 6}, Mariana C de Pinho^{3 6}, Leonardo J T Araujo¹⁸, Frederico S V Malta¹⁹, Aline B de Lima¹⁹, Joice do P Silva¹⁹, Danielle A G Zauli¹⁹, Alessandro C de S Ferreira¹⁹, Ricardo P Schnekenberg²⁰, Daniel J Laydon^{5 2}, Patrick G T Walker^{5 2}, Hannah M Schlüter¹⁶, Ana L P Dos Santos²¹, Maria S Vidal²¹, Valentina S Del Caro²¹, Rosinaldo M F Filho²¹, Helem M Dos Santos²¹, Renato S Aguiar²², José L Proença-Modena²³, Bruce Nelson²⁴, James A Hay^{25 26}, Mélodie Monod¹⁶, Xenia Miscouridou¹⁶, Helen Coupland^{5 2}, Raphael Sonabend^{5 2}, Michaela Vollmer^{5 2}, Axel Gandy¹⁶, Carlos A Prete Jr²⁷, Vitor H Nascimento²⁷, Marc A Suchard²⁸, Thomas A Bowden¹⁰, Sergei L K Pond²⁹, Chieh-Hsi Wu³⁰, Oliver Ratmann¹⁶, Neil M Ferguson^{5 2}, Christopher Dye⁴, Nick J Loman³¹, Philippe Lemey³², Andrew Rambaut⁹, Nelson A Fraiji^{7 33}, Maria do P S S Carvalho^{7 34}, Oliver G Pybus^#^{4 35}, Seth Flaxman^#¹⁶, Samir Bhatt^#^{1 2 36}, Ester C Sabino^#^{37 6}

Affiliations

¹ MRC Centre for Global Infectious Disease Analysis, School of Public Health, Imperial College London, London, UK. n.faria@imperial.ac.uk samir.bhatt@sund.ku.dk sabinoec@usp.br.
² The Abdul Latif Jameel Institute for Disease and Emergency Analytics (J-IDEA), School of Public Health, Imperial College London, London, UK.
³ Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
⁴ Department of Zoology, University of Oxford, Oxford, UK.
⁵ MRC Centre for Global Infectious Disease Analysis, School of Public Health, Imperial College London, London, UK.
⁶ Departamento de Moléstias Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
⁷ Fundação Hospitalar de Hematologia e Hemoterapia, Manaus, Brazil.
⁸ Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia, Manaus, Brazil.
⁹ Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK.
¹⁰ Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹¹ Departamento de Epidemiologia, Faculdade de Saúde Pública da Universidade de São Paulo, Sao Paulo, Brazil.
¹² Laboratório de Virologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil.
¹³ Institute for Applied Economic Research-Ipea, Brasília, Brazil.
¹⁴ Institute of Mathematics and Statistics, University of São Paulo, São Paulo, Brazil.
¹⁵ DB Diagnósticos do Brasil, São Paulo, Brazil.
¹⁶ Department of Mathematics, Imperial College London, London, UK.
¹⁷ Virology Research Centre, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
¹⁸ Laboratory of Quantitative Pathology, Center of Pathology, Adolfo Lutz Institute, São Paulo, Brazil.
¹⁹ Instituto Hermes Pardini, Belo Horizonte, Brazil.
²⁰ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
²¹ CDL Laboratório Santos e Vidal, Manaus, Brazil.
²² Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
²³ Laboratory of Emerging Viruses, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil.
²⁴ Instituto Nacional de Pesquisas da Amazônia, Manaus, Brazil.
²⁵ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
²⁶ Center for Communicable Disease Dynamics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
²⁷ Departamento de Engenharia de Sistemas Eletrônicos, Escola Politécnica da Universidade de São Paulo, São Paulo, Brazil.
²⁸ Department of Biomathematics, Department of Biostatistics, and Department of Human Genetics, University of California, Los Angeles, CA, USA.
²⁹ Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA, USA.
³⁰ Mathematical Sciences, University of Southampton, Southampton, UK.
³¹ Institute for Microbiology and Infection, University of Birmingham, Birmingham, UK.
³² Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
³³ Diretoria Clínica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas, Manaus, Brazil.
³⁴ Diretoria da Presidência, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas, Manaus, Brazil.
³⁵ Department of Pathobiology and Population Sciences, The Royal Veterinary College, London, UK.
³⁶ Section of Epidemiology, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
³⁷ Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. n.faria@imperial.ac.uk samir.bhatt@sund.ku.dk sabinoec@usp.br.

^# Contributed equally.

PMID:33853970
PMCID: PMC8139423
DOI: 10.1126/science.abh2644

Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil

Nuno R Faria et al. Science.2021.

.2021 May 21;372(6544):815-821.

doi: 10.1126/science.abh2644. Epub 2021 Apr 14.

Authors

Affiliations

¹ MRC Centre for Global Infectious Disease Analysis, School of Public Health, Imperial College London, London, UK. n.faria@imperial.ac.uk samir.bhatt@sund.ku.dk sabinoec@usp.br.
² The Abdul Latif Jameel Institute for Disease and Emergency Analytics (J-IDEA), School of Public Health, Imperial College London, London, UK.
³ Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
⁴ Department of Zoology, University of Oxford, Oxford, UK.
⁵ MRC Centre for Global Infectious Disease Analysis, School of Public Health, Imperial College London, London, UK.
⁶ Departamento de Moléstias Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
⁷ Fundação Hospitalar de Hematologia e Hemoterapia, Manaus, Brazil.
⁸ Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia, Manaus, Brazil.
⁹ Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK.
¹⁰ Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹¹ Departamento de Epidemiologia, Faculdade de Saúde Pública da Universidade de São Paulo, Sao Paulo, Brazil.
¹² Laboratório de Virologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil.
¹³ Institute for Applied Economic Research-Ipea, Brasília, Brazil.
¹⁴ Institute of Mathematics and Statistics, University of São Paulo, São Paulo, Brazil.
¹⁵ DB Diagnósticos do Brasil, São Paulo, Brazil.
¹⁶ Department of Mathematics, Imperial College London, London, UK.
¹⁷ Virology Research Centre, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
¹⁸ Laboratory of Quantitative Pathology, Center of Pathology, Adolfo Lutz Institute, São Paulo, Brazil.
¹⁹ Instituto Hermes Pardini, Belo Horizonte, Brazil.
²⁰ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
²¹ CDL Laboratório Santos e Vidal, Manaus, Brazil.
²² Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
²³ Laboratory of Emerging Viruses, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil.
²⁴ Instituto Nacional de Pesquisas da Amazônia, Manaus, Brazil.
²⁵ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
²⁶ Center for Communicable Disease Dynamics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
²⁷ Departamento de Engenharia de Sistemas Eletrônicos, Escola Politécnica da Universidade de São Paulo, São Paulo, Brazil.
²⁸ Department of Biomathematics, Department of Biostatistics, and Department of Human Genetics, University of California, Los Angeles, CA, USA.
²⁹ Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA, USA.
³⁰ Mathematical Sciences, University of Southampton, Southampton, UK.
³¹ Institute for Microbiology and Infection, University of Birmingham, Birmingham, UK.
³² Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
³³ Diretoria Clínica, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas, Manaus, Brazil.
³⁴ Diretoria da Presidência, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas, Manaus, Brazil.
³⁵ Department of Pathobiology and Population Sciences, The Royal Veterinary College, London, UK.
³⁶ Section of Epidemiology, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
³⁷ Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. n.faria@imperial.ac.uk samir.bhatt@sund.ku.dk sabinoec@usp.br.

^# Contributed equally.

PMID:33853970
PMCID: PMC8139423
DOI: 10.1126/science.abh2644

Abstract

Cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Manaus, Brazil, resurged in late 2020 despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1 acquired 17 mutations, including a trio in the spike protein (K417T, E484K, and N501Y) associated with increased binding to the human ACE2 (angiotensin-converting enzyme 2) receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7- to 2.4-fold more transmissible and that previous (non-P.1) infection provides 54 to 79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.

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Figures

**Fig. 1. SARS-CoV-2 epidemiological, diagnostic, genomic, and mobility data from Manaus.**
(A) Dark solid line shows the 7-day rolling average of the COVID-19 confirmed and suspected daily time series of hospitalizations in Manaus. Admissions in Manaus are from Fundao de Vigilncia em Sade do Amazonas (66). Green dots indicate daily severe acute respiratory mortality records from the SIVEP-Gripe (Sistema de Informao de Vigilncia Epidemiolgica da Gripe) database (67). Red dots indicate excess burial records based on data from Manaus Mayors office for comparison (supplementary materials, materials and methods). The arrow indicates 6 December 2020, the date of the first P.1 case identified in Manaus by our study. (B) Maximum likelihood tree (n = 962 viral genomes) with B.1.1.28, P.1, and P.2 sequences, with collapsed views of P.1 and P.2 clusters and highlighting other sequences from Amazonas state, Brazil. Ancestral branches leading to P.1 and P.2 are shown as dashed lines. A more detailed phylogeny is available in fig. S3. Scale bar is shown in units of nucleotide substitutions per site (s/s). (C) Number of air travel passengers from Manaus to all states in Brazil was obtained from National Civil Aviation Agency of Brazil (www.gov.br/anac). The ISO 3166-2:BR codes of the states with genomic reports of P.1 [GISAID (68), as of 24 February 2021], are shown in bold. An updated list of GISAID genomes and reports of P.1 worldwide is available athttps://cov-lineages.org/global_report_P.1.html. (D) Number of genome sequences from Manaus belonging to lineages of interest (supplementary materials, materials and methods). Spike mutations of interest are denoted.

**Fig. 2. Visualization of the time-calibrated maximum clade credibility tree reconstruction for B.1.1.28, P.1, and P.2 lineages in Brazil.**
Terminal branches and tips of Amazonas state are colored in brown, and those from other locations are colored in green (n = 962 viral genomes). Nodes with posterior probabilities of <0.5 have been collapsed into polytomies, and their range of divergence dates are illustrated as shaded expanses.

**Fig. 3. Temporal variation in the proportion of sequenced genomes belonging to P.1, and trends in quantitative RT-PCR Ct values for COVID-19 infections in Manaus.**
(A) Logistic function fitting to the proportion of genomes in sequenced infections that have been classified as P.1 (black circles, size indicating number of infections sequenced), divided up into time periods when the predicted proportion of infections that are due to P.1 is <1/3 (light brown), between 1/3 and 2/3 (green), and greater than 2/3 (gray). For the model fit, the darker ribbon indicates the 50% credible interval, and the lighter ribbon indicates the 95% credible interval. For the data points, the gray thick line is the 50% exact binomial CI, and the thinner line is the 95% exact binomial CI. (B) Ct values for genes E and N in a sample of symptomatic cases presenting for testing at a health care facility in Manaus (laboratory A), stratified according to the period defined in (A) in which the oropharyngeal and nasal swab collections occurred. (C) Ct values for genes E and N in a subsample of 184 infections included in (B) that had their genomes sequenced (dataset A).

**Fig. 4. Estimates of the epidemiological characteristics of P.1 inferred from a multicategory Bayesian transmission model fitted to data from Manaus, Brazil.**
(A) Joint posterior distribution of the cross-immunity and transmissibility increase inferred through fitting the model to mortality and genomic data. Gray contours indicate posterior density intervals ranging from the 95 and 50% isoclines. Marginal posterior distributions for each parameter shown along each axis. (B) As for (A), but showing the joint-posterior distribution of cross-immunity and the inferred relative risk of mortality in the period after emergence of P.1 compared with the period prior. (C) Daily incidence of COVID-19 mortality. Points indicate severe acute respiratory mortality records from the SIVEP-Gripe database (67,69). Brown and green ribbons indicate model fit for COVID-19 mortality incidence, disaggregated by mortality attributable to non-P.1 lineages (brown) and the P.1 lineage (green). (D) Estimate of the proportion of P.1 infections through time in Manaus. Black data points with error bars are the empirical proportion observed in genomically sequenced cases (Fig. 3A), and green ribbons (dark = 50% BCI, light = 95% BCI) are the model fit to the data. (E) Estimated cumulative infection incidence for the P.1 and non-P.1 categories. Black data points with error bars are reversion-corrected estimates of seroprevalence from blood donors in Manaus (2). Colored ribbons are the model predictions of cumulative infection incidence for non-P.1 lineages (brown) and P.1 lineages (green). These points are shown for reference only and were not used to fit the model. (F) Bayesian posterior estimates of trends in reproduction numberR_t for the P.1 and non-P.1 categories.

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Update of

Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus, Brazil.
Faria NR, Mellan TA, Whittaker C, Claro IM, Candido DDS, Mishra S, Crispim MAE, Sales FC, Hawryluk I, McCrone JT, Hulswit RJG, Franco LAM, Ramundo MS, de Jesus JG, Andrade PS, Coletti TM, Ferreira GM, Silva CAM, Manuli ER, Pereira RHM, Peixoto PS, Kraemer MU, Gaburo N Jr, Camilo CDC, Hoeltgebaum H, Souza WM, Rocha EC, de Souza LM, de Pinho MC, Araujo LJT, Malta FSV, de Lima AB, Silva JDP, Zauli DAG, de S Ferreira AC, Schnekenberg RP, Laydon DJ, Walker PGT, Schlüter HM, Dos Santos ALP, Vidal MS, Del Caro VS, Filho RMF, Dos Santos HM, Aguiar RS, Modena JLP, Nelson B, Hay JA, Monod M, Miscouridou X, Coupland H, Sonabend R, Vollmer M, Gandy A, Suchard MA, Bowden TA, Pond SLK, Wu CH, Ratmann O, Ferguson NM, Dye C, Loman NJ, Lemey P, Rambaut A, Fraiji NA, Carvalho MDPSS, Pybus OG, Flaxman S, Bhatt S, Sabino EC.Faria NR, et al.medRxiv [Preprint]. 2021 Mar 3:2021.02.26.21252554. doi: 10.1101/2021.02.26.21252554.medRxiv. 2021.Update in:Science. 2021 May 21;372(6544):815-821. doi: 10.1126/science.abh2644.PMID:33688664Free PMC article.Updated.Preprint.

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Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil

Affiliations

Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil

Authors

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Abstract

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Update of

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Grants and funding

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Medical

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